Sapropterin (also called tetrahydrobiopterin, or “BH4”) is a naturally occurring alkaloid of the pterin family. The biologically active stereoisomer of sapropterin has the chemical structure shown in Formula I:
Sapropterin can also exist in other tautomeric forms of the pyrimidine ring. The nomenclature of the bioactive stereoisomer of sapropterin is (6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(1H)-pteridinone, or (6R)-L-erythro-tetrahydrobiopterin, or 6R-BH4.
The chemical synthesis of sapropterin is well known. Access to the molecule has been accomplished by a variety of methods, using different starting materials to produce both the pterin ring structure portion of the molecule as well as the specific side chain required for pharmacological effect. Methods of synthesizing sapropterin are disclosed in, for example, U.S. Pat. Nos. 2,601,215; 3,505,329; 4,540,783; 4,550,109; 4,587,340; 4,595,752; 4,649,197; 4,665,182; 4,701,455; 4,713,454; 4,937,342; 5,037,981; 5,198,547; 5,350,851; 5,401,844; 5,698,408; and 5,698,408; and published Canadian Patent Application No. 2,420,374.
Pterins are bicyclic compounds that include a pyrazine ring and a pyrimidine ring having a carbonyl oxygen and an amino group. Pterins function as cofactors in enzymatic catalysis. Sapropterin functions as a cofactor for a number of different enzymes, including phenylalanine hydroxylase (PAH), tyrosine 3-hydroxylase, tryptophan 5-hydroxylase, and all three isoforms of nitric oxide synthase (NOS). Sapropterin also is a growth factor for Crithidia fasciculata, has proliferative activity in haemopoietic cells, and acts as a self-protecting factor for nitric oxide toxicity. These and other cofactor and cellular functions of sapropterin, as well as disorders relating to sapropterin deficiency, are disclosed in Thony et al., Biochem. J., 347:1-16 (2000). Disorders relating to sapropterin deficiency also are generally described in Blau et al., “Disorders of Tetrahydrobiopterin and Related Biogenic Amines,” in The Metabolic and Molecular Bases of Inherited Disease, 8th Ed., pp. 1275-1776, McGraw-Hill Publishing Co. (New York, N.Y., 2001).
The present disclosure provides a more efficient synthesis of sapropterin.